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191.
Using intact human platelets as the immunogen and a functional, collagen-coated bead agglutination assay, we have produced a murine monoclonal antibody (6F1) that blocks the interaction between platelets and collagen in the presence of Mg++. 6F1 affinity-purified the platelet glycoprotein Ia/IIa complex, and approximately 800 molecules of 6F1 bound per platelet at saturation. 6F1 nearly completely inhibited collagen-induced platelet aggregation and inhibited platelet adhesion to collagen by greater than 95% when plasma proteins were absent. Antibody 10E5, which blocks the binding of adhesive glycoproteins to GPIIb/IIIa, produced only minor inhibition (approximately 25%) of adhesion under the same circumstances. In contrast, when tested in platelet-rich plasma (PRP), 6F1 had only a minor effect on collagen-induced platelet aggregation, prolonging the lag phase but not the slope or maximum aggregation. Similarly, when collagen was precoated with plasma, 6F1 caused less inhibition of platelet adhesion (53%) than without the precoating (greater than 95%). Antibody 10E5 inhibited this adhesion by 32%, and the combination of 6F1 and 10E5 was more effective than either alone, inhibiting it by 90%. Time course studies of platelet agglutination of collagen-coated beads using PRP containing physiologic concentrations of divalent cations showed early inhibition by 6F1, indicating that the GPIa/IIa receptor operates in this environment. With more prolonged incubation, however, 6F1 was less effective; this later agglutination could be partially prevented by adding 10E5 or PGE1 to the 6F1. These data support a model wherein collagen can directly interact with GPIa/IIa and can indirectly interact with GPIIb/IIIa via intermediary adhesive proteins. The physiological significance of these interactions, and potential interactions with other receptors, remains to be established. 相似文献
192.
193.
The mechanism of thrombin-induced platelet factor 4 secretion 总被引:15,自引:1,他引:15
We have measured thrombin-induced secretion of platelet factor 4 antigen (PF4) and simultaneously followed its intracellular translocation by immunofluorescence. In permeable resting platelets, speckled intracellular immunofluorescent staining for PF4 was observed. Addition of thrombin to washed platelets at 22 degrees C resulted in secretion of PF4 and formation of large (approximately 0.5 micrometer) immunofluorescent masses. These masses moved to the cell periphery during secretion and were virtually absent at the conclusion of secretion. Ultrastructural examination of thrombin-treated platelets revealed vacuoles corresponding in size, shape, and time of occurrence to the large immunofluorescent masses of PF4. These vacuoles contained PF4 by immunoferritin staining of frozen thin sections; they therefore appear to represent the ultrastructural counterpart of the large PF4 masses. When intact cells were stained for PF4 after thrombin addition, only 5.6% of the large masses stained. Thus, during secretion, PF4 antigen is consolidated into large closed pools that appear as vacuoles in the electron microscope. 相似文献
194.
Immunolocalization of inducible nitric oxide synthase in synovium and cartilage in rheumatoid arthritis and osteoarthritis 总被引:8,自引:1,他引:8
Grabowski PS; Wright PK; Van 't Hof RJ; Helfrich MH; Ohshima H; Ralston SH 《Rheumatology (Oxford, England)》1997,36(6):651-655
Nitric oxide has been implicated as a mediator of inflammatory arthritis,
and recent work has shown that pro-inflammatory cytokines stimulate NO
production in vitro by activation of the inducible nitric oxide synthase
(iNOS) pathway. In order to identify the cellular sources of NO production
within the joint, we have used immunohistochemical techniques to study the
distribution of iNOS in synovium and cartilage from normal and diseased
joints. iNOS was most strongly expressed in the synovial lining layer,
subsynovium, vascular smooth muscle and chondrocytes from patients with
rheumatoid arthritis (RA). Analysis of serial sections, coupled with double
immunofluorescent staining, showed that the CD68+ macrophages in the
synovial lining layer and, to a lesser extent, fibroblasts were the
predominant source of iNOS within synovium, whereas T cells, B cells and
neutrophils were negative. A similar pattern of iNOS staining was seen in
osteoarthritis, but fewer cells were iNOS positive and the intensity of
staining, particularly in cartilage, was much weaker than in RA. In
contrast, no evidence of iNOS was detected in non- inflammatory synovium or
in cartilage derived from normal joints (fractured neck of femur). In
conclusion, these data support the hypothesis that synovium and cartilage
are important sources of increased NO production in patients with
inflammatory arthritis. Localization of iNOS at these sites within the
inflamed joint raises the possibility that increased local production of NO
may contribute to the pathogenesis of inflammatory arthritis by increasing
synovial blood flow and by modulating cellular function within synovium and
articular cartilage.
相似文献
195.
Chronic granulomatous disease (CGD) results from defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, central to which is the membrane-bound cytochrome b-245. The cytochrome is composed of two protein subunits, the larger (gp91-phox) being deficient in X-linked CGD. In this study, we have analyzed expression of the cytochrome subunits in B-cell lines from two autosomal CGD patients for whom the disease is caused by deficiency of p22-phox, the smaller subunit. We report the presence of a 65-kD precursor of gp91- phox in the membrane fraction of both p22-phox-deficient cell lines, corresponding to the core protein with N-linked carbohydrate side chains in the high mannose form. Expression of p22-phox in these cells resulted in functional correction of NADPH oxidase. In addition, gp91- phox in the reconstituted cells was processed to its terminally glycosylated form. These data suggest that the association of the 65-kD gp91-phox precursor with p22-phox is a prerequisite for processing of the carbohydrate side chains to the complex form in the Golgi. The detection of this precursor will enable characterization of mutations disrupting the subunit interaction (either naturally occurring or derived by in vitro mutagenesis) and so aid in structure-function analysis of cytochrome b-245. Reconstitution of p22-phox-deficient cells shows the potential of gene therapy for this autosomal form of CGD. 相似文献
196.
Spontaneous iron overload in alpha-thalassemic mice 总被引:1,自引:0,他引:1
Because clinical disorders of spontaneous iron overload have no experimental counterpart, we studied iron distribution (atomic absorption analysis) and intestinal absorption (59Fe) in mice with hereditary alpha-thalassemia. Mice heterozygous for a radiation-induced alpha-Hb gene deletion exhibit a mild hemolytic anemia, like the human condition, with microcytosis, reticulocytosis, splenomegaly, and chemical evidence of defective alpha-chain synthesis. Quantitative iron determination showed that total iron content in spleen, liver, and kidney, but not heart or lung, of adult alpha-thalassemic mice was greater (P less than .05) than that in unaffected littermates. Iron concentration was also increased in liver (P less than .001), spleen (P = .025), kidney (P = .058), and heart (P = .010); in general, the greater the iron concentration in liver, the greater that in spleen (r = .39, P = .009), kidney (r = .70, P less than .001), and heart (r = .46, P less than .001). In mice examined 8 months postoperatively, splenectomy, as compared to sham operation, significantly raised iron content in extrasplenic tissues, but did not affect total body iron. At 10-11 weeks of age, but no longer at 12-14 weeks, thalassemic mice showed higher rates of iron absorption than age-matched controls. Thus, alpha-thalassemic mice display an early occurring iron absorption defect, leading to a modest, sustained, nonprogressive iron overload, and thereby represent a valuable model for exploring disorders of iron homeostasis. 相似文献
197.
High frequency of N-ras activation in acute myelogenous leukemia 总被引:8,自引:0,他引:8
Using the NIH/3T3 cell transfection assay, activated cellular oncogenes have been detected in around 10% to 20% of human tumors. From a series of DNA preparations from tissues infiltrated with acute myelogenous leukemia (AML), 50% (3/6) caused transformation of NIH/3T3 cells. Thus AML appears to be the human tumor with the highest frequency of oncogenes detected by DNA transfection. In each case the oncogene involved was N-ras, a member of the ras gene family. Biologic and clinical parameters of AML patients with and without N-ras oncogenes in their tumors are discussed. 相似文献
198.
A pedigree was studied in which five individuals with beta-thalassemia minor were found to have nontransfusional hemochromatosis. Three were children under the age of 10 and two were young male adults, ages 28 and 33. A 5-yr-old child without evidence of thalassemia also had hemochromatosis. Since hemochromatosis is transmitted as an HLA-linked autosomal recessive disorder, HLA haplotypes serve as markers of hemochromatosis alleles. In this pedigree, five identifiable HLA haplotypes were associated with hemochromatosis alleles. Only individuals with two hemochromatosis alleles (homozygosity) had heavy iron loads, whether beta-thalassemia minor was present or not. Individuals with beta-thalassemia minor but without a hemochromatosis allele had normal transferrin saturation. A 65-yr-old man with beta- thalassemia minor and a single hemochromatosis allele had only a minimally elevated transferrin saturation (54%). The presence of beta- thalassemia minor did not appear to accentuate the degree of iron loading expected in individuals homozygous or heterozygous for hemochromatosis alleles. Our findings suggest that nontransfusional hemochromatosis found in association with beta-thalassemia minor is due primarily to homozygosity for hemochromatosis. 相似文献
199.
The cost of treatments especially in conditions where multiresistant bacteria are involved are a major issue in times where in most developed countries in the world payment systems based on diagnoses-related-groups (DRG) are in place. There is great evidence that especially the length of stay in hospital (LOS), the time in the intensive care unit (ICU-days) and the hours of mechanical ventilation (HMV) are major cost drivers. - While established methods of pharmacoeconomical analyses focus on the efficiency of drugs from healthcare system perspective, these data are often not sufficient for improving treatment strategies in a given hospital context. - We developed a system that allows the analysis of patients with severe infections on the basis of routine data that is also used for reimbursement. These data contain a lot of information concerning the clinical conditions. By using the ICD-coding we developed an algorithm which allows the detection of patients with infections and gives information on the potential financial outcome of these patients. By using the analysis it is possible to identify subsets of infections and the patient records that had a potentially negative DRG-result, i.e. the costs are higher than the reimbursement. When identified the patient records undergo a peer review, where the clinical situation and the antibiotic therapy are reviewed by medical experts. In case simulations it is possible to find out if a different therapeutic approach, e.g. by different choices in initial (empirical) antibiotic treatment would have caused other outcomes. - Data driven analyses together with peer reviews of patient records are a useful tool to examine antibiotic treatment strategies and to establish changes that again can be reviewed on a regular basis. Doing this a continous improvement process can be established in hospitals which can lead to a better balance of clinical and economical outcomes in patients with severe infections. Moreover these analyses are helpful in assessing the literature on economical benefits of new therapies. 相似文献
200.
T Herzog O Belyaev AM Chromik D Weyhe CA Mueller J Munding A Tannapfel W Uhl MH Seelig 《European journal of medical research》2010,15(7):292-296